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Drug Metabolism and Disposition Fast Forward
First published on June 30, 2004; DOI: 10.1124/dmd.104.000240

0090-9556/04/3210-1154-1161$20.00
DMD 32:1154-1161, 2004

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IDENTIFICATION AND METABOLISM OF A NOVEL DIHYDROHYDROXY-S-GLUTATHIONYL CONJUGATE OF A PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR AGONIST, MK-0767 [(±)-5-[(2,4-DIOXOTHIAZOLIDIN-5-YL)METHYL]-2-METHOXY-N-[[(4-TRIFLUOROMETHYL) PHENYL]METHYL]BENZAMIDE], IN RATS

Vijay Bhasker G. Reddy, George A. Doss, Mellissa Creighton, Christopher J. Kochansky, Stella H. Vincent, Ronald B. Franklin, and Bindhu V. Karanam

Department of Drug Metabolism, Merck Research Laboratories, Rahway, New Jersey

MK-0767 [(±)-5-[(2,4-dioxothiazolidin-5-yl)methyl]-2-methoxy-N-[[(4-trifluoromethyl)phenyl]methyl]benzamide] is a novel thiazolidinedione-containing peroxisome proliferator-activated receptor {alpha}/{gamma} agonist. In rats dosed orally with [14C]MK-0767, a dihydrohydroxy-S-glutathionyl conjugate of the parent compound was identified in the bile using liquid chromatography-mass spectometry and 1H NMR techniques. The formation of the conjugate likely proceeded via an arene oxide intermediate. The corresponding cysteinylglycine and cysteinyl conjugates likely formed from the further metabolism of the dihydrohydroxy-S-glutathionyl conjugate also were detected in rat bile. The dihydrohydroxy-S-glutathionyl conjugate was formed in vitro following the incubation of MK-0767 and glutathione with rat, dog, or monkey liver microsomes, and its formation was NADPH-dependent; however, this conjugate was not detected in human liver microsomal incubations. When incubated with rat intestinal contents, the dihydrohydroxy-S-glutathionyl conjugate was reduced to the parent compound (MK-0767), suggesting the involvement of intestinal microflora in its metabolism. There was no reduction of the conjugate by rat intestinal cytosol.

Address correspondence to: Dr. Vijay Bhasker G. Reddy, RY 80L-109, Merck Research Laboratories, 126 East Lincoln Avenue, Rahway, NJ 07065. E-mail: g_vijay_reddy{at}merck.com




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